The pharmacophore and stereochemistry Flashcards
how does drug action occur
for a drug molecule to exert a pharmacological effect, an interaction between the drug molecule and the target molecule must occur
when can bonding occur
can only occur if the key functional groups are structurally orientated so that they align appropriately with complementary functional groups on target molecule
what is a pharmacophore
ensemble of steric and electronic fearers that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger or block its biological response
what are pharmacophoric descriptors
used to define a pharmacore, including ionic, H bonding, hydrophobic and electrostatic interaction sites, defined by atoms, ring centres and virtual points
what are stereoisomers
isomers that possess identical constitution but which differ in the arrangement of their atoms in space
what is stereochemistry
branch of chemistry that deals with spatial arrangements of atoms in molecules and the effects of these arrangements on the chemical and physical properties of substances
what is chirality
a molecule is chiral if it is not superimposable on its mirror image regardless of how it is contorted
what are enantiomers
molecules that are mirror images of each other but aren’t identical
- rotate the plane of polarised light equally but in opposite directions
- also called optical isomers
- non superimposable mirror images
- have the same physicochemical properties in an achiral environment apart from optical rotation
what are diastereoisomers
all stereoisomers that are not enantiomers
- non superimposable non mirror images
- have different physicochemical properties
what do most drugs act on
a protein target
what are proteins composed of
amino acids
describe the structure of proteins
- have primary, secondary, tertiary and quaternary structure
- have a 3 dimensional structure which is determined by a combination of factors
what is the protein 3D structure determined by
- amino acid sequence and interactions between these amino acids
- interaction with other molecules in immediate environment
what is complementarity
the correspondence or similarity between nucleotides or strands of nucleotides of DNA and RNA molecules that allows precise pairing
- the affinity that an antigen and antibody have for each other as a result of the chemical arrangement of their combining sites
what is a binding site
a specific region in a molecular entity that is capable of entering into a stabilising interaction with another molecular entity
- eg. active site in an enzyme with its substrate
- typical forms of interaction are by hydrogen bonding, coordination and ion pair formation
what is the easson stedman hypothesis
if 2 enantiomers demonstrate different activities at the same target, then 3 sites on a molecule must be involved in the interaction between drug and target
- a 3 point interaction ensure stereoselectivity
what is a eutomer
the enantiomer of a chiral compound that is the more potent for a particular action
what is the consequence of single enantiomer medicines
any situation in which a chiral drug interacts with another chiral molecule could potentially have stereoselective consequences
what are the pharmacodynamic considerations in the interaction between drug molecule and target molecule
- no difference in activity
- eg. antiarrhythmic activity of propranolol is not stereoselective - quantitative differences
- distemper may have reduced activity compared to eutomer - qualitative differences
- enantiomers may act at different receptor sites - behaviour of racemate is different from either enantiomer
what are the pharmacokinetic differences in interaction between drug molecule and target molecule in absorption
- most synthetic drugs cross biological membranes by passive diffusion
- some are actively transported
what are the pharmacokinetic differences in interaction between drug molecule and target molecule in distribution
- protein binding
- S enantiomer of disopyramide shows lower plasma and renal clearance, longer half life and smaller volume of distribution than R isomer
what are the pharmacokinetic differences in interaction between drug molecule and target molecule in metabolism
- in propanolol, S isomer is the eutomer
- R isomer is more rapidly metabolised than S isomer in propanolol
what are the pharmacokinetic differences in interaction between drug molecule and target molecule in excretion
- for many drugs, this is a passive process
- might expect to see stereoselectivity for drugs that are actively secreted or reabsorbed
give examples of drug interactions with the S or R isomers
- cimetidine interacts selectively with the R enantiomer of warfarin
- phenylbutazone interacts selectively with S isomer of warfarin
describe the economics of enantiomers
generally cheaper to synthesise the racemate rather than a single enantiomer
what is cis-trans isomerism
points of rigidity within a molecule can result in more than 1 form of the molecule
- a double bond has restricted rotation
- can have cis and trans isomers
describe the different uses of tamoxifen and clomiphene
- Z tamoxifen is used in the treatment of oestrogen, dependent on breast cancer
- Z clomiphene is used in treatment of ovulatory failure
what is conformation
where spatial arrangement of atoms can be interconverted without breaking/remaking bonds
- rotation about single bonds
- small but measurable energy differences between conformers
give an example of conformation
thyroxine and triiodothyronine
what are the implications of conformation for drug design
- spatial arrangement of key functional groups is important
- seemingly minor changes to the structure can have consequences on the conformation of the molecule and the biological properties of the drug
